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1.
ACS Omega ; 6(10): 7181-7185, 2021 Mar 16.
Article in English | MEDLINE | ID: covidwho-1387156

ABSTRACT

Serine proteases neutrophil elastase (NE), protease 3 (PR3), cathepsin G (CatG), and neutrophil serine protease 4 (NSP4) are released by activated neutrophils swarming around the place of pathogen invasion to provoke an immune response. However, uncontrolled proteolytic activity of proteases results in various human diseases, including cardiovascular diseases, thrombosis, and autoimmunity. In addition, proteases can be hijacked by several viruses to prime virus-derived surface proteins and evade immune detection by entering into the host cell. Indeed, porcine elastase increases the suitability of host cells to be infected by SARS-CoV-1. We compared the cleavage sites of human NE, PR3, and CatG as well as porcine-derived trypsin within the amino acid sequence of the proteolytic sensitive activation loop at the interface of S1/S2 of the spike protein (S protein) of SARS-CoV-1 as well as SARS-CoV-2. As a result, NE and PR3, but not CatG, hydrolyze the scissile peptide bond adjacent to the polybasic amino acid sequence of the S1/S2 interface of SARS-CoV-2, which is distinctive from SARS-CoV-1. These findings suggest that neutrophil-derived NE and PR3 participate in priming of the S1/S2 interface during an immune response.

2.
Transbound Emerg Dis ; 68(4): 1721-1725, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1319349

ABSTRACT

Conventional piglets were inoculated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through different routes, including intranasal, intratracheal, intramuscular and intravenous ones. Although piglets were not susceptible to SARS-CoV-2 and lacked lesions or viral RNA in tissues/swabs, seroconversion was observed in pigs inoculated parenterally (intramuscularly or intravenously).


Subject(s)
COVID-19 , Swine Diseases , Animals , COVID-19/veterinary , Disease Models, Animal , Disease Susceptibility/veterinary , RNA, Viral , SARS-CoV-2 , Swine , Swine Diseases/virology
3.
Eur J Hosp Pharm ; 2021 May 19.
Article in English | MEDLINE | ID: covidwho-1236470

ABSTRACT

We report the case of a man in his early 70s with idiopathic acquired haemophilia A and persistent high-titre type II inhibitors on immunosuppressive treatment to eradicate the inhibitor. As complications, he had a nosocomial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which caused severe pneumonia and an explosive inflammatory reaction that required tocilizumab and remdesivir treatment, and a high-risk retroperitoneal haematoma. Recombinant porcine factor VIII, susoctocog alfa, was requested from the Pharmacy Service in view of the extreme risk of thromboembolism resulting from the concomitant inflammatory storm caused by SARS-CoV-2. Improvement in the SARS-CoV-2 infection made it possible to complete the immunosuppressive treatment with rituximab. The patient was discharged with mycophenolate mofetil as immunosuppressive treatment after 89 days in hospital and 22 days of treatment with susoctocog alfa. His SARS-CoV-2 infection resolved and the haematoma evolved favourably.

4.
Biochem Biophys Res Commun ; 553: 25-29, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1147359

ABSTRACT

The current COVID-19 pandemic is caused by infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A sex-bias has been observed, with increased susceptibility and mortality in male compared to female patients. The gene for the SARS-CoV-2 receptor ACE2 is located on the X chromosome. We previously generated TP53 mutant pigs that exhibit a sex-specific patho-phenotype due to altered regulation of numerous X chromosome genes. In this study, we explored the effect of p53 deficiency on ACE2 expression in pigs. First, we identified the p53 binding site in the ACE2 promoter and could show its regulatory effect on ACE2 expression by luciferase assay in porcine primary kidney fibroblast cells. Later, quantitative PCR and western blot showed tissue- and gender-specific expression changes of ACE2 and its truncated isoform in p53-deficient pigs. We believe these findings will broaden the knowledge on ACE2 regulation and COVID-19 susceptibility.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Gene Expression Regulation , Organ Specificity , Sex Characteristics , Sus scrofa/metabolism , Tumor Suppressor Protein p53/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Animals , Base Sequence , Binding Sites , COVID-19/metabolism , COVID-19/virology , Disease Models, Animal , Female , Fibroblasts , Gene Deletion , Male , Promoter Regions, Genetic/genetics , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics , X Chromosome/genetics
5.
Br J Pharmacol ; 178(3): 626-635, 2021 02.
Article in English | MEDLINE | ID: covidwho-1066635

ABSTRACT

BACKGROUND AND PURPOSE: Currently, there are no licensed vaccines and limited antivirals for the treatment of COVID-19. Heparin (delivered systemically) is currently used to treat anticoagulant anomalies in COVID-19 patients. Additionally, in the United Kingdom, Brazil and Australia, nebulised unfractionated heparin (UFH) is being trialled in COVID-19 patients as a potential treatment. A systematic comparison of the potential antiviral effect of various heparin preparations on live wild type SARS-CoV-2, in vitro, is needed. EXPERIMENTAL APPROACH: Seven different heparin preparations including UFH and low MW heparins (LMWH) of porcine or bovine origin were screened for antiviral activity against live SARS-CoV-2 (Australia/VIC01/2020) using a plaque inhibition assay with Vero E6 cells. Interaction of heparin with spike protein RBD was studied using differential scanning fluorimetry and the inhibition of RBD binding to human ACE2 protein using elisa assays was examined. KEY RESULTS: All the UFH preparations had potent antiviral effects, with IC50 values ranging between 25 and 41 µg·ml-1 , whereas LMWHs were less inhibitory by ~150-fold (IC50 range 3.4-7.8 mg·ml-1 ). Mechanistically, we observed that heparin binds and destabilizes the RBD protein and furthermore, we show heparin directly inhibits the binding of RBD to the human ACE2 protein receptor. CONCLUSION AND IMPLICATIONS: This comparison of clinically relevant heparins shows that UFH has significantly stronger SARS-CoV-2 antiviral activity compared to LMWHs. UFH acts to directly inhibit binding of spike protein to the human ACE2 protein receptor. Overall, the data strongly support further clinical investigation of UFH as a potential treatment for patients with COVID-19.


Subject(s)
Heparin/pharmacology , SARS-CoV-2/growth & development , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/pharmacology , COVID-19/drug therapy , Chlorocebus aethiops , Heparin/metabolism , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/pharmacology , Protein Binding/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Viral Plaque Assay
6.
Science ; 368(6494): 1016-1020, 2020 05 29.
Article in English | MEDLINE | ID: covidwho-45712

ABSTRACT

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) causes the infectious disease COVID-19 (coronavirus disease 2019), which was first reported in Wuhan, China, in December 2019. Despite extensive efforts to control the disease, COVID-19 has now spread to more than 100 countries and caused a global pandemic. SARS-CoV-2 is thought to have originated in bats; however, the intermediate animal sources of the virus are unknown. In this study, we investigated the susceptibility of ferrets and animals in close contact with humans to SARS-CoV-2. We found that SARS-CoV-2 replicates poorly in dogs, pigs, chickens, and ducks, but ferrets and cats are permissive to infection. Additionally, cats are susceptible to airborne transmission. Our study provides insights into the animal models for SARS-CoV-2 and animal management for COVID-19 control.


Subject(s)
Animals, Domestic , Betacoronavirus/physiology , Coronavirus Infections , Disease Models, Animal , Disease Susceptibility , Ferrets , Pandemics , Pneumonia, Viral , Animals , Antibodies, Viral/blood , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , COVID-19 , Cats , Chickens , Coronavirus Infections/transmission , Coronavirus Infections/virology , Dogs , Ducks , Feces/virology , Female , Male , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , RNA, Viral/isolation & purification , Respiratory System/virology , SARS-CoV-2 , Species Specificity , Sus scrofa , Virus Attachment , Virus Replication
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